The goal of this NIH SCORE proposal is to develop several novel synthetic methods to transform a cytotoxic marine-derived secondary metabolite into a potent chemotherapeutic agent for the treatment of leukemia. Worldwide, it is estimated that more than six people die every hour from some form of blood cancer. As a result of being a cancer that affects the blood, surgery is not an effective option, and modern-day therapies include radiation therapy and/or the administration of several chemotherapeutic agents. Since many patients cannot tolerate the high-dose regimen of drugs over time, new and effective agents that can be utilized in combination therapy and administered in low dosages over time are needed, especially in light of recent reports that question both the side-effects and efficacies of current drugs and drug-candidates used treat blood cancers. Recently, (+)-Taumycin A was isolated from a Madagascar sponge of genus Fascaplysinopsis and shown to inhibit UT-7 cell growth in the micromolar range (IC50=1M). In order to address the need for new blood- cancer treatments, a goal of this research program is to utilize total synthesis to supply a clinically-relevant amoun of this potent metabolite for further biological evaluation. The specific aims of this proposal are (1) to determine the unknown, absolute stereochemistry of (+)-taumycin A via total synthesis. This synthetic effort will lead to, (2) the development of a novel, one-pot metal-catalyzed method to regioselectively introduce a methyl substituent and an oxazole ring cis across a terminal alkyne by exploiting a carboalumination / paladium- mediated Suzuki cross coupling strategy. In addition, we will also explore (3) the stereoselective generation of a silyl ketene acetal and its use in an enantioselective vinylogous aldol reaction to establish two key stereocenters as well as to facilitate the final macrocyclic ring closure. Finally, (4) the synthetic route will offer acess to several analogs, and structural mimics that will assist in the determination of the unknown biological mode of action of this potential chemotherapeutic. Importantly, these novel methods will have application beyond the scope of the current proposal and are envisioned to be exploited in future total syntheses by the Maio laboratory, as our long-term goal is to be known as a strong and regular contributor to the chemical literature with a focus on the total synthesis of complex natural products that display both interesting molecular architecture and promising biological activity.